Therapeutic compositions and methods

ABSTRACT

Methods of promoting healing through enhanced regeneration of tissue (e.g. hard tissue or soft tissue) by contacting the tissue or the surrounding tissue with an anti-inflammatory agent. These methods are useful in a variety of dental and orthopedic applications.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/XXXXX, which was filed on Dec. 7, 1999 as U.S. patent applicationSer. No. 09/455,861, for which a petition under 37 C.F.R §1.53(c) toconvert the non-provisional application to a provisional application wasfiled on Dec. 6, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to the use of anti-inflammatoryagents to enhance the regeneration and healing of tissue (e.g. hardtissue and soft tissue).

BACKGROUND OF THE INVENTION

[0003] Polymers comprising aromatic or aliphatic anhydrides have beenstudied extensively over the years for a variety of uses. For example,in the 1930s fibers comprising aliphatic polyanhydrides were preparedfor use in the textile industry. In the mid 1950s, aromaticpolyanhydrides were prepared with improved film and fiber formingproperties. More recently, attempts have been made to synthesizepolyanhydrides with greater thermal and hydrolytic stability andsustained drug release properties.

[0004] U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the preparationof polyanhydrides with improved sustained drug release properties frompure, isolated prepolymers of diacids and acetic acid. However, thesebiocompatible and biodegradable aromatic polyanhydrides have aliphaticbonds resulting in compounds with slow degradation times as well asrelatively insoluble degradation products unless incorporated into acopolymer containing a more hydrophilic monomer, such as sebacic acid.The aromatic polyanhydrides disclosed in the '128 Patent and the '904Patent are also insoluble in most organic solvents. A bioerodiblecontrolled release device produced as a homogenous polymeric matrix frompolyanhydrides with aliphatic bonds having weight average molecularweights greater than 20,000 and an intrinsic velocity greater than 0.3dL/g and a biologically active substance is also described in U.S. Pat.No. 4,888,176. Another bioerodible matrix material for controlleddelivery of bioactive compounds comprising polyanhydride polymers with auniform distribution of aliphatic and aromatic residues is disclosed inU.S. Pat. No. 4,857,311.

[0005] Biocompatible and biodegradable aromatic polyanhydrides preparedfrom para-substituted bis-aromatic dicarboxylic acids for use on woundclosure devices are disclosed in U.S. Pat. No. 5,264,540. However, thesecompounds exhibit high melt and glass transition temperatures anddecreased solubility, thus making them difficult to process. Thedisclosed polyanhydrides also comprise radical or aliphatic bonds whichcannot be hydrolyzed by water.

[0006] Polyanhydride polymeric matrices have also been described for usein orthopedic and dental applications. For example, U.S. Pat. No.4,886,870 discloses a bioerodible article useful for prosthesis andimplantation which comprises a biocompatible, hydrophobic polyanhydridematrix. U.S. Pat. No. 5,902,599 also discloses biodegradable polymernetworks for use in a variety of dental and orthopedic applicationswhich are formed by polymerizing anhydride prepolymers.

[0007] Biocompatible and biodegradable aromatic polyanhydrides have nowbeen developed with improved degradation, processing and solubilityproperties, as well as therapeutic utilities. As demonstrated herein,the new aromatic polyanhydrides are particularly useful in enhancingregeneration and healing of tissue. Thus, these new polyanhydrides canbe used in a variety of dental and orthopedic applications.

SUMMARY OF THE INVENTION

[0008] It has unexpectedly been discovered that the local administrationof an anti-inflammatory agent to tissue provides beneficial effects onthe healing and growth of the tissue and on proximally located tissues.

[0009] Accordingly, the invention provides a method to promote healingof tissue comprising administering an effective amount of ananti-inflammatory agent to or near the tissue.

[0010] The invention provides a method to promote healing of hard tissuecomprising administering an effective amount of an anti-inflammatoryagent to the hard tissue or to soft tissue near the hard tissue.

[0011] The invention also provides a method of treating periodontaldisease comprising administering an effective amount of ananti-inflammatory agent at the site of the periodontal disease.

[0012] The invention also provides a method of treating a bone fracturecomprising fixing the fracture with an orthopedic device comprising ananti-inflammatory agent.

[0013] The invention also provides a method to enhance regeneration oftissue comprising administering an effective amount of ananti-inflammatory agent to or near the tissue.

[0014] The invention also provides a method to enhance regeneration ofbard tissue comprising administering an effective amount of ananti-inflammatory agent to the hard tissue or to soft tissue near thehard tissue.

[0015] The invention also provides a method to decrease bone resorptionat a site in the body of a patient comprising administering an effectiveamount of an anti-inflammatory agent at or near the site.

[0016] The invention also provides a method to promote healing of bonecomprising contacting the bone and surrounding soft tissue with anaromatic polyanhydride comprising a repeating unit having the structure:

[0017] wherein Ar is a substituted or unsubstituted aromatic ring and Ris —Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group,wherein R₁ is a difunctional organic moiety and Z₁ is a difunctionalmoiety selected from the group consisting of esters, amides, urethanes,carbamates and carbonates so that regeneration of bone is enhanced.

[0018] The invention also provides a method of treating periodontaldiseases in a patient comprising administering to the patient at thesite of the periodontal disease an aromatic polyanhydride comprising arepeating unit having the structure:

[0019] wherein Ar is a substituted or unsubstituted aromatic ring and Ris —Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group,wherein R₁ is a difunctional organic moiety and Z₁ is a difunctionalmoiety selected from the group consisting of esters, amides, urethanes,carbamates and carbonates.

[0020] The invention also provides a method of treating bone fracturesin a patient comprising fixing the bone fracture with an orthopedicdevice comprised of or coated with an aromatic polyanhydride comprisinga repeating unit having the structure:

[0021] wherein Ar is a substituted or unsubstituted aromatic ring and Ris —Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group,wherein R₁ is a difunctional organic moiety and Z₁ is a difunctionalmoiety selected from the group consisting of esters, amides, urethanes,carbamates and carbonates.

[0022] The invention also provides pharmaceutical compositionscomprising an anti-inflammatory agent and a pharmaceutically acceptablecarrier, which are formulated to provide controlled release of the agentat or near tissue (e.g. hard or soft tissue). Preferably, thecompositions are formulated to provide local release of an effectiveamount of the agent over a period of at least about 2, about 5, about10, about 20, or about 40 days. The compositions can also preferably beformulated to provide local release of an effective amount of the agentover a period of up to about 3 months, about 6 months, about 1 year, orabout 2 years.

[0023] The invention also provides the use of an anti-inflammatory agentto prepare a medicament useful for promoting the healing of tissue byadministration to or near the tissue.

[0024] The invention also provides the use of an anti-inflammatory agentto prepare a medicament useful for decreasing bone resorption at a sitein the body of a mammal by administration at or near the site.

[0025] The invention also, provides the use of an anti-inflammatoryagent to prepare a medicament useful to enhance regeneration of tissueby administration to or near the tissue.

[0026] The preparation of aromatic polyanhydrides from ortho-substitutedbis-aromatic carboxylic acid anhydrides disrupts the crystallinity ofthe resulting polymer, enhancing solubility and processability, as wellas degradation properties: The use of hydrolyzable bonds such as esters,amides, urethanes, carbamates and carbonates as opposed to aliphaticbonds in these compounds further enhances these properties.

[0027] These aromatic polyanhydrides have a repeating unit within thestructure of Formula I:

[0028] wherein Ar is a substituted or unsubstituted aromatic ring and Ris a difunctional organic moiety substituted on each Ar ortho to theanhydride group. Ar and R are preferably selected so that the hydrolysisproducts of the polyanhydrides have a the chemical structure of ananti-inflammatory agent, particularly salicylates such as aspirin,non-steroidal anti-inflammatory compounds, or other aromaticanti-inflammatory compounds. Ar is preferably a phenyl group and R ispreferably —Z₁—R₁—Z₁— in which R₁, is a difunctional moiety and both Z₁sare independently either an ester —C(═O)O—, amide —C(═O)N—, anhydride—C(═O)—O—C(═O)—, carbonate —O—C(═O)—O—, urethane —N—C(═O)—N—, or sulfide—S— groups. R₁ is preferably an alkylene group containing from 1 to 20carbon atoms, or a group with 2-20 carbon atoms having a structureselected from (—CH₂—CH₂—O—)_(m), —(CH₂—CH₂—CH₂—O—)_(m) and(—CH₂—CHCH₃—O—)_(m).

[0029] Ortho-substituted bis-aromatic carboxylic acid anhydrides of thepresent invention are used in the preparation of the aromaticpolyanhydrides of the present invention. The ortho-substitutedbis-aromatic carboxylic acid anhydrides have the structure of FormulaII:

[0030] wherein Ar and R, and the preferred species thereof, are the sameas described above with respect to Formula I and R is substituted oneach Ar ortho to the anhydride group.

[0031] The aromatic polyanhydrides of the present invention meet theneed for moldable biocompatible biodegradable polymers and areparticularly useful in enhancing the healing process of bone andsurrounding soft tissue.

[0032] Accordingly, the present invention relates to compositions andmethods of using compositions comprising a aromatic polyanhydride with arepeating unit of Formula I to enhance healing of tissue (e.g. hardtissue); It has been found that these compositions promote healing inhard tissue by inhibiting inflammation and/or pain in the surroundingsoft tissues and by enhancing hard tissue regeneration by promotinggrowth and/or by reducing bone resorption. To use these compositions toenhance tissue regeneration, it is preferred that the compositions beincorporated into fibers, films, membranes, pastes or microspheres. Forthis use, it is also preferred that the compositions comprisepoly(anhydride-esters), referred to herein as bioactive polyanhydridesthat degrade into salicylic acid, an anti-inflammatory, antipyretic andanalgesic agent. The hard tissue and surrounding soft tissue aredirectly contacted with the composition so that regeneration and healingis enhanced.

[0033] A more complete appreciation of the invention and other intendedadvantages can be readily obtained by reference to the followingdetailed description of the preferred embodiments and claims, whichdisclose the principles of the invention and the best modes which arepresently contemplated for carrying them out.

BRIEF DESCRIPTION OF THE FIGURES

[0034]FIG. 1 illustrates a perspective view of a bioactive implant asconstructed in accordance with one embodiment

DETAILED DESCRIPTION OF THE INVENTION

[0035] Applicant has discovered that the local administration of ananti-inflammatory agent on or near hard tissue, such as bone or tooth,enhances the growth and regeneration of the hard tissue and thesurrounding soft tissue. Preferably, the anti-inflammatory agent isadministered in a form that provides a controlled release of the agentat or near the hard tissue over a period of days or months.

[0036] Numerous controlled release mechanisms are known in the art (forexample see R. Langer, 1990, ScienceI, 249, 1527-1533. Any controlledrelease mechanism can be used in conjunction with the methods of theinvention, provided it allows for the controlled release of theanti-inflammatory agent at or near the site of the tissue. One preferredmethod for providing the controlled release of an anti-inflammatoryagent is to incorporate the agent into a polymer (e.g. a bio-degradablepolymer). The agent can be dispersed through the polymer matrix, can beappended to the backbone of the polymer, or can be incorporated directlyinto a biodegradable polymer backbone. Typically, any anti-inflammatoryagent can be dispersed through a polymer matrix to provide a suitablecontrolled release formulation. However, the ability of an agent to beappended to or incorporated into a polymer may depend on the functionalgroups present in the agent. Preferred anti-inflammatory agents that canbe appended to or incorporated into a polymer to provide a suitablecontrolled release formulation are described in greater detail below.

[0037] Anti-inflammatory Agent

[0038] Anti-Inflammatory agents are a well known class of pharmaceuticalagents which reduce inflammation by acting on body mechanisms (Stedman'sMedical Dictionary 26 ed., Williams and Wilkins, (1995); Physicians DeskReference 51 ed., Medical Economics, (1997)).

[0039] Anti-inflammatory agents useful in the methods of the inventioninclude Non-steroidal Anti-Inflammatory Agents (NSAIDS). NSAIDStypically inhibit the body's ability to synthesize prostaglandins.Prostaglandins are a family of hormone-like chemicals, some of which aremade in response to cell injury. Specific NSAIDS approved foradministration to humans include naproxen sodium, diclofenac, sulindac,oxaprozin, diflunisal, aspirin, piroxicam, indomethocin, etodolac,ibuprofen, fenoprofen, ketoprofen, mefenamic acid, nabumetone, tolmetinsodium, and ketorolac trometharmine.

[0040] Other anti-inflammatory agents useful in the methods of theinvention include salicylates, such as, for example, salicilic acid,acetyl salicylic acid, choline salicylate, magnesium salicylate, sodiumsalicylate, olsalazine, and salsa late.

[0041] Other anti-inflammatory agents useful in the methods of theinvention include cyclooxygenase (COX) inhibitors. COX catalyzes theconversion of arachidonate to prostaglandin H2 (PGH2); a COX inhibitorinhibits this reaction. COX is also known as prostaglandin H synthase,or PGH synthase. Two Cox genes, Cox-1 and Cox-2 have been isolated inseveral species. COX-2 is tightly regulated in most tissues and usuallyonly induced in abnormal conditions, such as inflammation, rheumatic andosteo-atrhitis, kidney disease and osteoporosis COX-1 is believed to beconstitutively expressed so as to maintain platelet and kidney functionand integral homeostasis. Typical COX inhibitors useful in the methodsof the invention include etodolac, celebrex, meloxicam, piroxicam,nimesulide, nabumetone, and rofecoxib.

[0042] Preferred anti-inflammatory agents that can be incorporated intoa polymer matrix for administration in the methods of the inventioninclude: Isonixin, Amtolmetin Guacil, Proglumetacin, Piketoprofen,Difenamizole, Epirizole, Apazone, Feprazone, Morazone, Phenylbutazone,Pipebuzone, Propyphenazone, Ramifenazone, Thiazolinobutazone, Aspirin,Benorylate, Calcium Acetylsalicylate, Etersalate, Imidazole Salicylate,Lysine Acetylsalicylate, Morpholine Salicylate, 1-Naphthyl Salicylate,Phenyl Acetylsalicylate, Ampiroxicam, Droxicam, S-Adenosylmethionine,Amixetrine, Benzydamine, Bucolome, Difenpiramide, Emorfazone,Guaiazulene, Nabumetone, Nimesulide, Proquazone, Superoxide Dismutase,and Tenidap.

[0043] Preferred anti-inflammatory agents that can be appended to apolymer for administration in the methods of the invention include:Etofenamate, Talniflumate Terofenamate, Acemetacin, Alclofenac,Bufexamac, Cinmetacin, Clopirac, Felbinac, Fenclozic Acid, Fentiazac,Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, MetiazinicAcid, Mofezolac, Oxametacine, Pirazolac, Sulindac, Tiaramide, Tolmetin,Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin, Clidanac,Ketorolac, Tinoridine, Benoxaprofen, Bermoprofen, Bucloxic Acid,Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam,Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pirprofen,Pranoprofen, Protizinic Acid, Suprofen, Tiaprofenic Acid, Zaltoprofen,Benzpiperylon, Mofebutazone, Oxyphenbutazone, Suxibuzone,Acetaminosalol, Parsalmide, Phenyl Salicylate, Salacetamide,Salicylsulfuric Acid, Isoxicam, Lomoxicam, Piroxicam, Tenoxicam,ε-Acetamidocaproic Acid, Bendazac, α-Bisabolol, Paranyline, Perisoxal,and Zileuton.

[0044] Preferred anti-inflammatory agents that can be incorporated intoa polymer backbone for administration in the methods of the inventioninclude: Enfenamic Acid, Aceclofenac, Glucametacin, Alminoprofen,Carprofen, Ximoprofen, Salsalate, 3-Amino-4-hydroxybutyric Acid,Ditazol, Fepradinol, and Oxaceprol.

[0045] Preferred anti-inflammatory agents that posses suitable orthofunctionality to be incorporated into the backbone of a polymer offormula (I) as described herein include: Flufenamic Acid, MeclofenamicAcid, Mefenamic Acid, Niflumic Acid, Tolfenamic Acid, Amfenac,Bromfenac, Diclofenac Sodium, Etodolac, Bromosaligenin, Diflunisal,Fendosal, Gentisic Acid, Glycol Salicylate, Salicilic Acid, Mesalamine,Olsalazine, Salicylamide O-Acetic Acid, Sulfasalazine,

[0046] For any anti-inflammatory agent referred to herein by a tradename it is to be understood that either the trade name product or theactive ingredient possessing anti-inflammatory activity from the productcan be used. Additionally, preferred agents identified herein forincorporation into a polymer backbone can also preferably be appended toa polymer or can be incorporated into a polymer matrix. Preferred agentsthat can be appended to a polymer can also preferably be incorporatedinto a polymer matrix.

[0047] Definitions

[0048] As used herein the term “hard tissue” includes tissue that hasbecome mineralized, such as, for example, bone, cartilage, and tooth.

[0049] As used herein, administering an agent “to or near the tissue”means administering the agent so that it is in direct contact with thetissue or administering the agent to a location proximal to tissue, sothat the agent can produce the desired or stated therapeutic effect.

[0050] As used herein, “administering an anti-inflammatory agent to hardtissue” means applying the agent so that it is in direct contact withthe hard tissue.

[0051] As used herein, “administering an anti-inflammatory agent to thesoft tissue near hard tissue” means applying the agent to the softtissue proximal to the hard tissue, so that the agent can produce thedesired or stated therapeutic effect.

[0052] As used herein the term, “formulated for controlled release”means that the agent is formulated such that it will be released over anextended period of time when administered according to the methods ofthe invention. For example, the agent can conveniently be formulated sothat it will be released over a period of at least about 2, about 5,about 10, about 20, or about 40 days. Preferably, the agent isformulated so that it is released over at least about 5 or about 10days. The agent can also preferably be formulated so that it is releasedover a period of about 30 to about 90 days. For the treatment of hardtissue, the agent is preferably formulated so that it is released over aperiod of about 30 to about 90 days. For the treatment of soft tissue,the agent is preferably formulated so that it is released over a periodof about 1 to about 30 days, more preferably about 2 to about 25 days.

[0053] As used herein, an agent is “appended” to a polymer when theagent is bonded to the polymer as a side chain or side group, but is notpart of the polymer backbone. Preferably, the agent is bonded to thepolymer through a linkage that is suitable to release the agent when thepolymer is administered according to the methods of the invention. Forexample, the agent can conveniently be linked to a polymer through ahydrolyzable linkage such as an anhydride or ester linkage.

[0054] As used herein, the tern “dispersed through the polymer matrix”means that an anti-inflammatory agent is located within the matrix of apolymer such that it can be released in a controlled fashion within thebody. Preferably, the polymer matrix comprises a biodegradable polymer.

[0055] As used herein, the term “at the site of the periodontal disease”means at a site that is at or proximal to the site of the periodontaldisease, such that when an agent is administered to the site, the agentcan produce a beneficial effect and ameliorate one or more symptoms ofthe periodontal disease.

[0056] As used herein, the term “gingival cleft” means the space betweenthe soft tissue of the gum and the tooth.

[0057] As used herein, the term “fixing the fracture” means to hold thefractured pieces together or to stabilize the fracture.

[0058] As used herein, the term “enhance regeneration of hard tissue”means to allow or to facilitate the growth of the hard tissue in anormal manner.

[0059] As used herein, “administering an anti-inflamnatory agent at thesite” means applying the agent so that it is in direct contact with thesite.

[0060] As used herein, “administering an anti-inflammatory agent nearthe site” means applying the agent proximal to the site, so that theagent can produce the desired or stated therapeutic effect (e.g. reducebone resorption at the site).

[0061] As used herein, the term “periodontal disease” includes anyabnormality, either inflammatory or degenerative, of the tissue aroundthe tooth.

[0062] As used herein, the term “healing” means the restoration tonormal health.

[0063] Aromatic polyanhydrides with improved degradation properties andprocessability have now been developed These compounds have repeatingunits with the structure of Formula I:

[0064] wherein Ar is a substituted or unsubstituted aromatic ring and Ris a difunctional organic moiety substituted on each Ar ortho to theanhydride group. Ar and R are preferably selected so that the hydrolysisproducts of the polyanhydrides have a chemical structure resemblingpharmaceutically-active materials, particularly salicylates such asaspirin, non-steroidal anti-inflammatory naphthyl or phenyl propionatessuch as ibuprofen, ketoprofen, naproxen, and the like, or other aromaticanti-inflammatory compounds such as indomethacin, indoprofen, and thelike. In particular, Ar is preferably a phenyl group and R is preferably—Z₁—R₁—Z₁— in which R₁, is a difunctional moiety and both Z₁s areindependently either an ester, amide, anhydride, carbonate, urethane orsulfide groups. R₁ is preferably an alkylene group containing from 1 to20 carbon atoms, or a group with 2-20 carbon atoms having a structureselected from (—CH₂—CH₂—O—)_(m), (CH₂—CH₂—CH₂—O—)_(m) and(—CH₂—CHCH₃—O—)_(m) or R₁ may have the structure —R₂—Z₂—R₃—1 wherein R₂and R₃ are independently alkylene groups containing from 1 to 19 carbonatoms or groups having from 2 to 18 carbon atoms having a structureselected from (—CH₂—CH₂—O—)_(m), (—CH₂—CH₂—CH₂—O—)_(m), and(—CH₂—CHCH₃—O—)_(m), and Z₂ is selected from the difunctional moietiesdescribed above with respect to Z₁.

[0065] Ar may be an alkylaryl group, in which a difunctional organicmoiety is positioned between each anhydride carbonyl group and thecorresponding aromatic ring. Preferably, however, each carbonyl group isdirectly substituted on the corresponding aromatic ring.

[0066] Preferred polymers of the present invention have repeating unitswith the structure of Formula I in which Ar is a phenyl ring and R isselected from —Z₁—(—CH₂—)_(m)Z₁—, —Z₁(—CH₂—CH₂—O—)_(m), —Z₁—,—Z₁(—CH₂—CH₂—CH₂—O—)_(m)—Z₁—, and —Z₁(—CH₂—CHCH₃—O—)_(m)—Z₁—, wherein Z₁is an ester or amide group and n is from 1 to 20 inclusive, andpreferably is 6, and m is selected so that R has from 2 to 20, andpreferably 6, carbon atoms.

[0067] A preferred polymer useful in the methods of the invention is apolymer of Formula I:

[0068] wherein Ar is a substituted or unsubstituted aromatic ring and Ris a difunctional organic moiety. R is preferably —Z₁—R₁—Z₁— in whichR₁, is a difunctional moiety and each Z₁ is independently an ester—C(═O)O—, amide —C(═O)N—, anhydride—C(═O)—O—C(═O)—, carbonate—O—(═O)—O—, urethane —N—C(═O)—N—, or thioester —C(═O)S—. R₁ ispreferably an alkylene group containing from 1 to 20 carbon atoms.

[0069] The aromatic polyanhydrides of the present invention may beprepared by the method described in Conix, Macromol. Synth., 2, 95-99(1996), in which dicarboxylic acids are acetylated in an excess ofacetic anhydride followed by melt condensation of the resultingcarboxylic acid anhydride at 180° C. for 2-3 hours. The resultingpolymers are isolated by precipitation into diethyl ether from methylenechloride. The described process is essentially the conventional methodfor polymerizing bis-aromatic dicarboxylic acid anhydrides into aromaticpolyanhydrides.

[0070] Aromatic polyanhydrides in accordance with the present inventionhave average molecular weights of about 1500 daltons, up to about 50,000daltons, calculated by Gel Permeation Chromatography (GPC) relative tonarrow molecular weight polystyrene standards. Preferred aromaticpolyanhydrides have average molecular weights of about 1500 daltons, upto about 35,000 daltons.

[0071] The aromatic polyanhydrides of the present invention are producedfrom ortho-substituted bis-aromatic carboxylic acid anhydrides havingthe structure of Formula II:

[0072] in which Ar, R and the preferred species thereof are the same asdescribed above with respect to Formula I. As noted above,ortho-substituted bis-aromatic carboxylic acid anhydrides are preparedby acetylation of the corresponding ortho-substituted bis-aromaticcarboxylic acids in an excess of acetic anhydride. The dicarboxylicacids have the structure of Formula III

[0073] wherein Ar, R and the preferred species thereof are the same asdescribed above with respect to Formula I.

[0074] The dicarboxylic acids are prepared by reacting a stoichiometricratio of aromatic carboxylic acid having the structure Z₃—Ar—COOH and acompound having a structure Z₄—R—Z₄ wherein Ar is a substituted orunsubstituted aromatic ring on which Z₃ is substituted ortho to thecarboxylic acid group, R is a difunctional organic moiety and Z₃ and Z₄are functional groups selected to provide the linkage desired betweenthe difunctional organic moiety and the two aromatic rings.

[0075] Suitable Z₃ and Z₄ functional groups, and the manner in whichthey may be reacted to produce the bis-aromatic dicarboxylic acids ofthe present invention, may be readily determined by those of ordinaryskill in the art without undue experimentation. For example, foraromatic polyanhydrides having the structure of Formula I in which Ar isa phenyl group and R is —O—(CH₂—)₆—O—, the ortho-substitutedbis-aromatic dicarboxylic acid starting material may be prepared byreacting o-salicylic acid with 1,6dibromohexane. For aromaticpolyanhydrides having the structure of Formula I in which Ar is a phenylgroup and R is —O—C(═O)—(CH₂—)₆—C(═O)—O—, the ortho-substitutedbis-aromatic dicarboxylic acid starting material may be prepared byreacting o-salicylic acid with 1,6dioctanoic acid.

[0076] The aromatic polyanhydrides used in the present invention can beisolated by known methods commonly employed in the field of syntheticpolymers to produce a variety of useful articles with valuable physicaland chemical properties. The new polymers can be readily processed intopastes, and gels or solvent cast to yield films, membranes, coatings,microspheres, chips and fibers with different geometric shapes fordesign of various medical implants, and may also be processed bycompression molding and extrusion. Medical implant applications includethe use of aromatic polyanhydrides to form shaped articles such asvascular grafts and stents, bone plates, sutures, implantable sensors,implantable drug delivery devices, stents for tissue regeneration,scaffolding for supporting new cell growth and other articles thatdecompose harmlessly within a known time period. For the presentinvention, it is preferred that the polyanhydride be incorporated intofilms, membranes, pastes, gels, microspheres, chips or fibers useful indental and orthopedic applications.

[0077] It has now been demonstrated that the polymers comprising thesearomatic polyanhydrides having a repeating unit with the structure ofFormula I in which Ar and R are selected to provide aromaticpolyanhydrides that hydrolyze to form therapeutically useful salicylatesare particularly useful in enhancing regeneration of tissue. Examples ofthe therapeutically useful salicylates include, but are not limited to,thymotic acid, 4,4sulfinyldinailine, 4-sulfanilamidosalicylic acid,sulfanilic acid, sulfanilylbenzylamine, sulfaloxic acid, succisulfone,salicylsulfuric acid, salsallate, salicylic alcohol, salicilic acid,orthocaine, mesalamine, gentisic acid, enfenamic acid, cresotic acid,aminosalicylic acid, aminophenylacetic acid, acetylsalicylic acid, andthe like. The identification of Ar and R moieties that provide aromaticpolyanhydrides that hydrolyze to form such therapeutically usefulsalicylates can be readily determined by those of ordinary skill in theart without undue experimentation.

[0078] A preferred salicylate for incorporation into the polymers offormula (I) is salicylic acid, thymotic acid, 4-sulfanilamidosalicylicacid, mesalamine, gentisic acid, enfenamic acid, cresotic acid, oraminosalicylic acid.

[0079] The quantity of aromatic polyanhydride that hydrolyzes to form anamount of therapeutic salicylate effective to relieve inflammation andpromote healing of bone can be readily determined by those of ordinaryskill in the art without undue experimentation. The quantity essentiallycorresponds stoichiometrically to the amount of salicylate known toproduce an effective treatment. Oral dosage forms of aromaticpolyanhydrides that hydrolyze to form other therapeutic non-steroidalanti-inflammatory compounds and other therapeutic compounds are preparedand administered in a similar manner.

[0080] Most degradable or absorbable devices for dental or orthopedicapplications cause local inflammation. In the present invention,however, use of compositions such as films, membranes, fibers, pastes,gels and microspheres comprising an aromatic polyanhydride thathydrolyzes to form a therapeutically useful salicylate in dental andorthopedic applications actually decreases local inflammation and/orpain. These compositions can also be incorporated into matrices toprovide preformed or adaptable scaffolding for cell ingrowth. Further,it has been found that use of these compositions promotes the healingprocess of the tissue (e.g. bone) through enhanced regeneration of thesetissues. Selection of the form of the composition to be used isperformed routinely by those of skill in the art based upon the type ofinjury and the tissue healing to be promoted.

[0081] Compositions comprising an aromatic polyanhydride can be used tocoat orthopedic devices for fixation of bone fractures such as pins orscrews, thereby decreasing the local inflammation and bone resorptionassociated with these devices. Films comprising an aromaticpolyanhydride are also believed to be useful as orthopedic devices toenhance the healing process of bone fractures.

[0082] Fibers useful as suture materials can also be comprised of thearomatic polyanhydride. For example, polymer fibers are used frequentlyin oral surgery to suture cleft palates. Use of an aromaticpolyanhydride which degrades to a therapeutic salicylate would enhancethe regeneration of the tissue via the sutures while decreasing the painand inflammation associated with the surgery via the degradationproducts.

[0083] Films, membranes, pastes, gels, chips and microspheres comprisingthe aromatic polyanhydrides can also be used to decrease dental pain andpromote healing within a tooth, in the pulp chamber and root canal.

[0084] Films or membranes comprising the aromatic polyanhydrides canalso be used in guided bone or tissue regeneration. Following surgery,especially oral or dental surgery, proper healing of the wound requiresboth bone and soft tissue regeneration. It is well known, however, thatbone heals more slowly than the surrounding tissues such as the gums. Infact, oftentimes ingrowth of other tissues into an area prevents therequired regeneration of the bone. For example, removal of a substantialportion of the tooth root due to resorption or disease leaves a cavitywhich is oftentimes quickly filled by connective tissue. This ingrowthof connective tissue effectively prevents bone regeneration.

[0085] Accordingly, a procedure referred to as guided bone or tissueregeneration has been developed to overcome this difficulty. In thismethod, a membrane is surgically inserted around the periphery of thewound cavity. The membrane prevents or inhibits the invasion of thewound cavity by unwanted cells types and allows the preferred cells togrow into the cavity, thereby healing the wound. This procedure is alsoused to regenerate bone around teeth and on edentulous jaw ridges inassociation with implant reconstruction.

[0086] Two membranes commonly used in guided tissue regeneration includea synthetic, non-resorbable polytetrafluoroethylene membrane such asGORETEX and synthetic membranes formed from glycolide and lactidecopolymers. U.S. Pat. No. 5,837,278 also describes a resorbable collagenmembrane for use in guided tissue regeneration. It is believed thatfilms comprising aromatic polyanhydrides would also be useful in thisprocedure.

[0087] Compositions comprising an aromatic polyanhydride that hydrolyzesto form a therapeutically useful salicylate are believed to beparticularly useful in treatment of periodontal diseases. Periodontaldiseases, including a group of related microbial-induced chronicinflammatory disorders and a disorder referred to periodontaldehiscence, destroy the tissue supporting the teeth. These diseases canresult in loss of normal soft and hard tissue architectures at sitesadjacent to the affected teeth. Incorporation of these compositions intofilms, membranes, pastes, fibers or microspheres for use in treatment ofperiodontal disease is expected to accelerate the recovery/restorationof new healthy periodontal architecture while reducing post-operativepain after periodontal surgery. Further, the lower pH environment whichresults from degradation into salicylates is unfavorable to growth ofsomeperiodontic bacteria. Thus, use of these compositions is alsoexpected to decrease infections in periodontal procedures.

[0088] In vivo studies were conducted to compare the affects of apolymer system of the present invention (referred to herein as thebioactive polymer or implant) and a chemically similar polyanhydridesystem (referred to herein as the control polyanhydride) on the healingprocess. The sole chemical difference between these two systems is thereplacement of the ether bond in the polyanhydride of the bioactivepolymer with an ester bond thereby resulting in degradation to salicylicacid as compared to a non-active component in the control polyanhydride.In these experiments, the polymers were compression-molded into filmswith thicknesses of 0.1, 0.2 and 0.3 mm and cut into 0.5 mm wide strips.

[0089] In these experiments, mice (n=10) were anesthetized and thepalatal gingival mucosa adjacent to the maxillary first molar wasreflected to expose the palatal and alveolar bone. A polymer film wasthen placed on the bone adjacent to the tooth. The tissue wasrepositioned and the procedure was repeated on the contra lateral side.Polymer films were randomly placed (left vs. right) with each mousecarrying both polymers. Mice were fed a ground diet and water ad libitumand weighed weekly. Mice were sacrificed at 1, 4 and 20 days postsurgical insertion.

[0090] Visual intraoral examination of the mucosa covering theimplantation sites was performed with a dissecting microscope underoptimum lighting. Magnification was varied from 5 to 40 times normalsize. Photographs were taken to record the morphological changesobserved.

[0091] Polymer membranes of thicknesses 0.1 and 0.2 mm were not visibleunder the microscope at 4 and 20 days post insertion. However, thickermembranes (0.3 mm) were still observable after 20 days. For the controlpolyanhydride films, the mucosa was red and thin near the implant withthe surrounding tissue inflamed at days 1 and 4. By day 14, the tissuewas slightly puffy in three animals while the tissue was within normallimits for the remaining 5 animals. In contrast, the tissue surroundingthe bioactive polymer implants was slight puffy after day 1 but withinnormal limits in all animals by day 4. Further, considerable swellingwas observed on the side bearing the control polyanhydride, whereas theside with the bioactive polymer showed a progressively normal mucosa.The tissue surrounding the control polyanhydride was very swollen andwhite, whereas the tissue adjacent to the bioactive implant was lessswollen and normal in color. The three maxillary molar palatal ridges(anterior, middle and posterior) were clearly visible. However, theanterior and middle ridges coalesced because of the swelling andblanching on the control polyanhydride side. This effect was mostpronounced at day 13. By days 15 and 20, blanching and swelling on thecontrol polyanhydride side were considerably diminished.

[0092] Histological examination of tissues from the mice was alsoperformed. After sacrifice, tissues were fixed in 10% formalin,decalcified, embedded in paraffin, sectioned serially at 4 μm thickness,and stained with hematoxylin and eosin. The sections were subjected tomicroscopic evaluation and histometric assessment using 4, 10 and 20×magnifications. The histopathological examination correlated well withvisual observations.

[0093] One mouse was sacrificed 24 hours post implantation. Thehistology showed heavy infiltration of polymorphonuclear (PMN)leucocytes and erythrocytes. The 0.1 mm films were mostly dissolvedduring the tissue processing procedure. The bone was denuded from theperitoneum and the polymer was in direct contact. The gingivalepithelium and connective tissue below the subcular epithelium wasbroken. The coronal part of the periodontal ligament linking thealveolar bone to the coronal cementum was mostly intact. The method forreflecting the palatal mucosa was effective in not damaging theperiodontal ligament below the level of the bone and coronal cementum.There was no significant difference between the bioactive and controlside except for the decrease in swelling on the bioactive side.

[0094] Two mice were sacrificed four days post implantation. At thistime point, some polymeric material remained in all sites. The 0.1 mmfilm was in direct contact with the palatal bone. An extensive, thinlayer of palatal epithelium was observed that surrounded portions of thepolymer specimens. The extent of the epithelium along the membranes wasgreater for the bioactive than for the control polyanhydride site.Similarly, the PMN cells inflammatory infiltrate was greater on thecontrol polyanhydride side than on the bioactive polymer side. Theinfiltrate was denser below the epithelium adjacent to the membrane. Theinfiltrate along the palatal bone was much less.

[0095] Six mice were sacrificed at twenty days post implantation. Atthis time point, small remnants of a 0.3 mm film in only one specimenwere present; all other specimens were devoid of polymer. Gingivalepithelium including subcular and junctional were essentially restoredon all sites. Two specimens showed external resorption that involvedcementum and dentin on the controll polyanhydride side. Tissue specimenswith bioactive polymer showed no alveolar bone, cementum and dentinresorption. However, a significant amount of new bone could be observedcoronal to the reversal lines in the sites bearing bioactive films. Newbone was also found in the control polyanhydride sites, but atinsignificant amounts as compared to the bioactive polymer side.Inflammatory cell infiltrate was present and consisted primarily of PMNcells and macrophages. No erythrocytes were observed except within thevasculature. The intensity of the infiltrate was lower on the bioactivepolymer sites.

[0096] Quantitative analyses were also performed via electronic imagestaken of the tissue sections using a Kodak MDS-120 camera attached to anOlympus CH-triocular microscope at magnifications of 4×, 10× and 40×.Using NIH Images 1.61 software, the area of bone, connective tissue,epithelium and artifacts at the lowest magnification were determined.Perpendicular to the widest part of the tooth, a square box was drawnwith sides 575 pixels in length. The areas of bone, connective tissue,epithelium and artifacts were determined by the number of pixels withinthe defined box. All images were blindly analyzed. Sections were takenfrom mice sacrificed after 20 days from membranes that were either 0.3or 2 mm thick. Results are shown in the following Table. Bone Area BoneArea Polymer (0.3 mm) (0.2 mm) Control Polyanhydride 94,750 85,563Bioactive Polymer 129,637 99,702

[0097] These experiments demonstrate that implantation of a filmcomprising an aromatic polyanhydride that hydrolyzes to form atherapeutically useful salicylate resulted in less swelling in tissuesadjacent to the film and a decrease in the density of inflammatory cellsas compared to other polyanhydride films. Further, little or no boneresorption was observed in the regions near the film as indicated byincreased thickness of the palatal. In fact, data from quantitativeanalyses are indicative of compositions used in the present inventioneither promoting bone growth or decreasing bone resorption relative tothe polyanhydride composition. Accordingly, use of compositionscomprising an aromatic polyanhydride that hydrolyzes to form atherapeutically useful salicylate in dental and osteopathic applicationsenhances the healing process of bone as compared to other polymersystems routinely used in these applications.

[0098] The invention also provides for bioactive implants which areuseful for treating periodontal disease. As shown in FIG. 1, a bioactiveimplant 100 comprises a film of material which is sized and shaped to bereceived in or near the gingival cleft. For instance, the film has aheight 102 of about 1-2 mm, a width 104 of about 1-5 mm, and a thickness106 of about 0.1-2.0 mm. It should be noted, however, that othersuitably sized films may be configurable to be received in or near thegingival cleft. Other examples for the bioactive implant 100 include,but are note limited to membranes, pastes, gels, chips, or microspheres.The bioactive agent further includes an anti-inflammatory agent, forinstance, any of the agents discussed above. Options for theanti-inflammatory agent include, but are not limited to, coatings,agents molded in or with a polymer matrix, or agents embedded in apolymer.

[0099] The following non-limiting examples set forth hereinbelowillustrate certain aspects of the invention. All parts and percentagesare by weight unless otherwise noted and all temperatures are in degreesCelsius. Except for acetic anhydride and ethyl ether (FisherScientific), all solvents and reagents were obtained from AldrichChemical. All solvents were HPLC grade. All other reagents were ofanalytical grade and were purified by distillation or recrystallization.

[0100] All compounds were characterized by a proton nuclear magneticresonance (NMR) spectroscopy, infrared (IR) spectroscopy, gel permeationchromatography (GPC), high performance liquid chromatography (HPLC),differential scanning calorimetry (DSC), and thermal gravimetricanalysis (TGA). Infrared spectroscopy was preformed on an ATI MattsonGenesis (M100) FTIR Spectrophotometer. Samples were prepared by solventcasting on NaCl plates. ¹H and ¹³CNMR spectroscopy was obtained on aVarian 200 MHZ or Varian 400 MHZ spectrometer in solutions of CDCl₃ orDMSO-d₆ with solvent as the internal reference.

[0101] GPC was performed on a Perkin-Elmer Advanced LC Sample Processor(ISS 200) with PE Series 200 LC pump and a PE Series LC Refractive IndexDetector to determine molecular weight and polydispersity. The dataanalysis was carried out using Turbochrom 4 software on a DEC Celebris466 computer. Samples were dissolved in tetrahydrofuran and elutedthrough a mixed bed column (PE PL gel, 5 μm mixed bed) at a flow rate of0.5 mL/minute. Samples (about 5 mg/mL) were dissolved into thetetrahydrofuran and filtered using 0.5 μm PTFE syringe filters prior tocolumn injection. Molecular weights were determined relative to narrowmolecular weight polystyrene standards (Polysciences, Inc.).

[0102] Thermal analysis was performed on a Perkin-Elmer systemconsisting of a TGA 7 thermal gravimetric analyzer equipped with PE AD-4autobalance and Pyris 1 DSC analyzer. Pyris software was used to carryout data analysis on a DEC Venturis 5100 computer. For DSC, an averagesample weight of 5-10 mg was heated at 10° C./minute at a 30 psi flow ofN₂. For TGA, an average sample weight of 10 mg was heated at 20°C./minute under a 8 psi flow of N₂. Sessile drop contact anglemeasurements were obtained with an NRL Goniometer (Rame-hart) usingdistilled water. Solutions of polymer in methylene chloride (10%wt/volume) were spun-coated onto glass slips, at 5,000 rpm for 30seconds.

EXAMPLES Example 1 Preparation of 1,6-Bis(o-Carboxyphenoxy) HexaneDicarboxylic Acid

[0103] To a mixture of salicylic acid (77.12 g, 0.5580 mole) anddistilled water (84 mL) sodium hydroxide (44.71 g, 1.120 mole) wasadded. The reaction was brought to reflux temperature before1,6dibromohexane (45.21 g, 0.2790 mole) was added drop-wise. Reflux wascontinued for 23 hours after which additional sodium hydroxide (11.17 g,0.2790 mole) was added. The mixture was refluxed for 16 more hours,cooled, filtered, and washed with methanol. The yield was 48.8%.

Example 2 Preparation of 1,6-Bis(o-Carboxyphenoxy) Hexane Monomer(o-CPH)

[0104] The dicarboxylic acid of Example 1 was acetylated in an excess ofacidic anhydride at reflux temperature. The resulting monomer wasprecipitated with methylene chloride into an excess of diethyl ether.The yield was 66.8%.

Example 3 Preparation of Poly(1,6-Bis(o-Carboxyphenoxy) Hexane)(Poly(o-CPH))

[0105] The monomer of Example 2 was polymerized in a melt condensationperformed at 180° C. for 3 hours under vacuum in a reaction vessel witha side arm.

[0106] The polymerization vessel was flushed with nitrogen at frequentintervals. The polymer was isolated by precipitation into diethyl etherfrom methylene chloride. The yield was quantitative.

[0107] All compounds were characterized by nuclear magnetic resonancespectroscopy, GPC, differential scanning calorimetry (DSC), thermalgravimetric analysis, contact angle measurements, UV spectroscopy, massspectroscopy, elemental analysis and high pressure liquid chromatography(HPLC).

[0108] The o-CPH monomer was polymerized by melt polycondensation for 60minutes at temperatures ranging from 100° C. to 300° C. Analysis of theresulting polymers by GPC indicated that the highest molecular weight,coupled with the lowest polydispersity index occurred at 260° C.

[0109] The poly(o-CPH) was generally soluble in methylene chloride andchloroform, while the poly(p-CPH) was not. The poly(o-CPH) was slightlysoluble in tetrahydrofuran, acetone and ethyl acetate.

[0110] Disks of poly(o-CPH), poly(p-CPH) and, as a reference,poly(lactic acid glycolic acid) were prepared and placed in 0.1phosphate buffer solution at 37° C. for 4 weeks. The degradation mediawas replaced periodically. The degradation profile was linear up tothree weeks time. In prior art polyanhydride systems, the aromaticgroups are para-substituted. This substitution pattern results in highermelt and glass transition temperatures and decreased solubility, thusultimately making these parasubstituted polymers difficult to process.

[0111] Poly(o-CPH), unlike poly(p-CPH), has both a lower melting point(65° C. vs. 143° C.) and glass transition temperature (35° C. vs. 47°C.). It is also possible to solution cast poly(o-CPH) using low-boilingsolvents whereas poly(p-CPH) is relatively insoluble in most organic andaqueous solvents. This structural modification gives a polymer whosehydrolysis products are chemically similar to aspirin. Aspirin is ananti-inflammatory agent derived from salicylic acid, which is one of thereagents used to synthesize the inventive polyanhydrides. Therefore, thedegradation products of this polymer actually aid in patient recovery.Because of pliability and ease of processing, the aromaticpolyanhydrides of the present invention have great potential as polymerscaffolds for wound healing.

Example 4 Preparation of 1,3-bis(o-carboxyphenoxy)propane dicarboxylicacid

[0112] 1,3-dibromopropane (14.7 mL, 0.145 mole) was added to a mixtureof salicylic acid (40.0 g, 0.290 mole), distilled water (44 mL) andsodium hydroxide (23.2 g, 0.580 mole) using the method described inExample 1. After 4 hours, additional sodium hydroxide (5.79 g, 0.145mole) was added to the reaction mixture. Reflux was continued foranother 4 hours, after which the mixture was cooled, filtered and washedusing the methods described in Example 1. The yield was 37.7%

Example 5 Preparation of poly(1,3-bis(o-carboxyphenoxy)propane)

[0113] The dicarboxylic acid of Example 4 was acetylated using themethods of Example 2. The acetylated dicarboxylic acid was thenpolymerized using the methods described in Example 3. The resultingpolymer had a M_(w) of 8,500 daltons and a polydispersity of 2.3.

[0114] Contact angle measurements on solvent-cast films demonstratedthat the hexyl chain of the polymer of Example 3 increased the surfacehydrophobicity relative to the shorter propyl chain of the polymer ofExample 5. A comparison of thermal characteristics emphasized theeffects of lengthening the alkyl chain. In particular, the polymer ofExample 3 has a T_(g) of 34° C. and a T_(d) of 410° C., while thepolymer of Example 5 had a T_(g) of 50° C. and a T_(d) of 344° C. Thus,the hexyl chain decreased the glass transition temperature (T_(g))relative to the propyl chain, reflecting the increased flexibility ofthe polymer chain. The opposite trend was observed for decompositiontemperatures (T_(d)), with the longer alkyl chain increasing the T_(d).

[0115] Optimum polycondensation conditions were determined for thepolymer of Example 3. Optimum conditions were defined as those thatyielded a crude polymer with the highest molecular weight and highestT_(g). Higher reaction temperatures decreased the M_(w) values (measuredby GPC) with a concurrent increase in polydispersity. As expected for acondensation polymerization, longer reaction times yielded polymers withhigher molecular weights. However, over longer reaction times, thereappeared a subsequent decrease in T_(g). Based on these results, theoptimum conditions were defined as temperatures of 220° C. for 150minutes under a vacuum.

Example 6 Preparation of 1,8-bis[o-(benzylcarboxy) carboxyphenyl] octanedicarboxlic acid ester

[0116] The initial synthesis of poly(anhydride-ester) dicarboxylic acidmonomers was attempted using the same methodology used for thepoly(anhydride-ether) dicarboxylic monomers of Example 3. It was found,however, that the reactivity of the phenol was enhanced by benzylationof the carboxylic acid group. In addition, the solubility of benzylsalicylate in organic media increased the ability of the reaction tomove forward.

[0117] Thus, benzyl salicylate (1.530 g, 6.720 mmole) and distilledtetrahydrofuran were combined under an inert atmosphere in a reactionflask. An ice-salt bath was placed under the reaction flask and theaddition of 60% sodium hydride (0.4840 g, 12.10 mmole) followed. Afterone hour, sebacoyl chloride (0.7850 g, 3.280 mmole) was added drop-wiseto the 0° C. reaction mixture. After 30 minutes, the reaction mixturewas vacuum filtered, the filtrate collected and the solvent removed toyield the free carboxylate as a white solid residue. Purification wasperformed using a chromatron with ethyl acetate/methylene chloride(20/80) as the solvent system. The yield was 43%.

Example 7 Polymerization of Poly(1,8-bis(o-dicarboxyphenyl) octane)

[0118] To remove the benzyl protecting groups, the1,8-bis[(benzylcarboxy)carboxyphenyl]octane dicarboxylic acid ester ofExample 6 (0.06000 g, 0.9620 mmole) was dissolved in methylene chloridein a reaction flask (60.00 mL). The catalyst Pd-C (10%, 1.200 g) wasadded to the reaction flask and hydrogen was bubbled through thesolution. After 30 minutes, the reaction was complete. The reactionmixture was filtered and the solvent removed to yield the freedicarboxylic acid as a white solid residue which was recrystallizedusing petroleum ether and methylene chloride. The yield was 45%.

[0119] The dicarboxylic acid was acetylated using the methods describedin Example 2 and the acetylated dicarboxylic acid was then polymerizedusing the methods described in Example 3. The resulting polymer had aM_(w) of 3,000 daltons and a polydispersity of 1.40.

[0120] Subsequent polymerizations yielded polymers with M_(w)'s rangingfrom 2,000 to 5,000 daltons with corresponding polydispersities ofapproximately 1.40.

[0121] The poly(anhydride esters) of Example 7 were compression moldedinto circular discs and placed in phosphate buffered saline solutionunder acidic, neutral and basic conditions. Over the course of athree-week degradation study, the polymers in the acidic and neutralsolutions showed no observable changes, whereas the polymer in the basicmedia showed significant morphological changes over time.

Example 8 Preparation of Poly[(1,8-bis (o-dicarboxyphenyl)octane)-(1,6-bis (p-carboxyphenoxy) hexane] copolymers

[0122] The 1,8-bis(o-dicarboxyphenyl) octane of Example 2 wascopolymerized with 1,6-bis(p-carboxyphenoxy) hexane using the methodsdescribed in Example 3. In an in vivo mouse study, each mouse wasimplanted with 2 polymers, the copolymer of Example 8 andpoly(1,6-bis(p-carboxyphenoxy) hexane). Each polymer was compressionmolded for 1 to 5 minutes at 1 to 20 K psi depending on the thickness ofpolymer needed. The polymer was placed under the palatal gingival mucosaadjacent to the first maxillary molars.

[0123] All publications, patents, and patent documents (including U.S.patent application Ser. Nos. 09/455,861 and 09/5b8,217; as well asInternational Patent Application PCT/US98/18816) are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques.

[0124] However, it should be understood that many variations andmodifications may be made while remaining within the spirit and scope ofthe invention.

What is claimed is:
 1. The use of an anti-inflammatory agent to preparea medicament useful for treating periodontal disease by administrationat the site of the periodontal disease.
 2. The use of claim 1 whereinthe agent is a salicylate.
 3. The use of claim 1 wherein the agent is anon-steroidal anti-inflammatory compound.
 4. The use of claim 1 whereinthe agent is an aromatic anti-inflammatory compound.
 5. The use of claim1 wherein the agent is a cyclooxygenase inhibitor.
 6. The use of claim 1wherein the agent is a cyclooxygenase-1 inhibitor.
 7. The use of claim 1wherein the agent is a cyclooxygenase-2 inhibitor.
 8. The use of claim 1wherein the agent is etodolac, celebrex, meloxicam, piroxicam,nimesulide, nabumetone, or rofecoxib.
 9. The use of claim 1 wherein theagent is formulated for controlled release at the site of theperiodontal disease.
 10. The use of claim 9 wherein the agent isincorporated in the matrix of a biodegradable polymer.
 11. The use ofclaim 10 wherein the agent is Isonixin, Amtolmetin Guacil,Proglumetacin, Piketoprofen, Difenamizole, Epirizole, Apazone,Feprazone, Morazone, Phenylbutazone, Pipebuzone, Propyphenazone,Ramifenazone, Thiazolinobutazone, Aspirin, Benorylate, CalciumAcetylsalicylate, Etersalate, Imidazole Salicylate, LysineAcetylsalicylate, Morpholine Salicylate, 1-Naphthyl Salicylate, PhenylAcetylsalicylate, Ampiroxicam, Droxicam, S-Adenosylmethionine,Amixetrine, Benzydamine, Bucolome, Difenpiramide, Emorfazone,Guaiazulene, Nabumetone, Nimesulide, Proquazone, Superoxide Dismutase,or Tenidap.
 12. The use of claim 10 wherein the polymer comprisesanhydride bonds in the polymer backbone.
 13. The use of claim 10 whereinthe polymer is a polyanhydride comprising a repeating unit having thestructure:

wherein Ar is a substituted or unsubstituted aromatic ring and R is—Z₁—R₁— substituted on each Ar ortho to the anhydride group, wherein R₁is a difunctional organic moiety and Z₁ is a difunctional moietyselected from the group consisting of esters, amides, urethanes,carbamates and carbonates.
 14. The use of claim 9 wherein the agent isappended to a biodegradable polymer.
 15. The use of claim 14 wherein theagent is Etofenamate, Talniflumate Terofenamate, Acemetacin, Alclofenac,Bufexamac, Cinmetacin, Clopirac, Felbinac, Fenclozic Acid, Fentiazac,Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, MetiazinicAcid, Mofezolac, Oxametacine, Pirazolac, Sulindac, Tiaramide, Tolmetin,Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin, Clidanac,Ketorolac, Tinoridine, Benoxaprofen, Bermoprofen, Bucloxic Acid,Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam,Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pirprofen,Pranoprofen, Protizinic Acid, Suprofen, Tiaprofenic Acid, Zaltoprofen,Benzpiperylon, Mofebutazone, Oxyphenbutazone, Suxibuzone,Acetaminosalol, Parsalmide, Phenyl Salicylate, Salacetamide,Salicylsulfuric Acid, Isoxicam, Lomoxicam, Piroxicam, Tenoxicam,ε-Acetamidocaproic Acid, Bendazac, α-Bisabolol, Paranyline, Perisoxal,or Zileuton.
 16. The use of claim 1 wherein the agent is administeredafter periodontal surgery.
 17. The use of claim 14 wherein the polymercomprises anhydride bonds in the polymer backbone.
 18. The use of claim14 wherein the polymer is a polyanhydride comprising a repeating unithaving the structure:

wherein Ar is a substituted or unsubstituted aromatic ring and R is—Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group, whereinR₁ is a difunctional organic moiety and Z₁ is a difunctional moietyselected from the group consisting of esters, amides, urethanes,carbamates and carbonates.
 19. The use of claim 9 wherein the agent isincorporated into the backbone of a biodegradable polymer.
 20. The useof claim 19 wherein the agent is Enfenamic Acid, Aceclofenac,Glucametacin, Alminoprofen, Carprofen, Ximoprofen, Salsalate,3-Amino-4-hydroxybutyric Acid, Ditazol, Fepradinol, or Oxaceprol. 21.The use of claim 19 wherein the polymer comprises anhydride bonds in thepolymer backbone.
 22. The use of claim 19 wherein the polymer is anaromatic polyanhydride.
 23. The use of claim 19 wherein the polymer is apolyanhydride comprising a repeating unit having the structure:

where Ar is a substituted or unsubstituted aromatic ring and R is—Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group, whereinR₁ is a difunctional organic moiety and Z₁ is a difunctional moietyselected from the group consisting of esters, amides, urethanes,carbamates and carbonates.
 24. The use of claim 19 wherein Ar isFlufenamic Acid, Meclofenamic Acid, Mefenamic Acid, Niflumic Acid,Tolfenamic Acid, Amfenac, Bromfenac, Diclofenac Sodium, Etodolac,Bromosaligenin, Diflunisal, Fendosal, Gentisic Acid, Glycol Salicylate,Mesalamine, Olsalazine, Salicylamide O-Acetic Acid, Salicilic Acid,Sulfasalazine,
 25. The use of claim 19 wherein the polymer isincorporated into a film, paste, gel, fiber, chip, microsphere orscaffolding for cell ingrowth.
 26. The use of claim 23 wherein each Z₁is an ester.
 27. An orthopedic device comprising an anti-inflammatoryagent that is formulated for controlled release.
 28. The device of claim27 wherein the agent is incorporated in the matrix of a biodegradablepolymer.
 29. The device of claim 28 wherein the agent is Isonixin,Amtolmetin Guacil, Proglumetacin, Piketoprofen, Difenamizole, Epirizole,Apazone, Feprazone, Morazone, Phenylbutazone, Pipebuzone,Propyphenazone, Ramifenazone, Thiazolinobutazone, Aspirin, Benorylate,Calcium Acetylsalicylate, Etersalate, Imidazole Salicylate, LysineAcetylsalicylate, Morpholine Salicylate, 1-Naphthyl Salicylate, PhenylAcetylsalicylate, Ampiroxicam, Droxicam, S-Adenosylmethionine,Amixetrine, Benzydamine, Bucolome, Difenpiramide, Emorfazone,Guaiazulene, Nabumetone, Nimesulide, Proquazone, Superoxide Dismutase,or Tenidap.
 30. The use of claim 28 wherein the polymer comprisesanhydride bonds in the polymer backbone.
 31. The device of claim 28wherein the polymer is a polyanhydride comprising a repeating unithaving the structure:

where Ar is a substituted or unsubstituted aromatic ring and R is—Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group, whereinR₁ is a difunctional organic moiety and Z₁ is a difunctional moietyselected from the group consisting of esters, amides, urethanes,carbamates and carbonates.
 32. The device use of claim 28 wherein theagent is appended to a biodegradable polymer.
 33. The use of claim 32wherein the agent is Etofenamate, Talniflumate Terofenamate, Acemetacin,Alclofenac, Bufexamac, Cinmetacin, Clopirac, Felbinac, Fenclozic Acid,Fentiazac, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac,Metiazinic Acid, Mofezolac, Oxametacine, Pirazolac, Sulindac, Tiaramide,Tolmetin, Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin,Clidanac, Ketorolac, Tinoridine, Benoxaprofen, Bermoprofen, BucloxicAcid, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam,Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pirprofen,Pranoprofen, Protizinic Acid, Suprofen, Tiaprofenic Acid, Zaltoprofen,Benzpiperylon, Mofebutazone, Oxyphenbutazone, Suxibuzone,Acetaminosalol, Parsalmide, Phenyl Salicylate, Salacetamide,Salicylsulfuric Acid, Isoxicam, Lomoxicam, Piroxicam, Tenoxicam,ε-Acetamidocaproic Acid, Bendazac, α-Bisabolol, Paranyline, Perisoxal,or Zileuton.
 34. The device of claim 32 wherein the polymer comprisesanhydride bonds in the polymer backbone.
 35. The device of claim 32wherein the polymer is a polyanhydride comprising a repeating unithaving the structure:

wherein Ar is a substituted or unsubstituted aromatic ring and R is—Z₁—R₁—Z₁— substituted on each Ar ortho to the anhydride group, whereinR₁ is a difunctional organic moiety and Z₁ is a difunctional moietyselected from the group consisting of esters, amides, urethanes,carbamates and carbonates.
 36. The device of claim 28 wherein the agentis incorporated into the backbone of a biodegradable polymer.
 37. Thedevice of claim 36 wherein the agent is Enfenamic Acid, Aceclofenac,Glucametacin, Alminoprofen, Carprofen, Ximoprofen, Salsalate,3-Amino4-hydroxybutyric Acid, Ditazol, Fepradinol, or Oxaceprol.
 38. Thedevice of claim 36 wherein the polymer comprises anhydride bonds in thepolymer backbone.
 39. The device of claim 36 wherein the polymer is anaromatic polyanhydride.
 40. The device of claim 36 wherein the polymeris a polyanhydride comprising a repeating unit having the structure:

wherein Ar is a substituted or unsubstituted aromatic ring and R is—Z₁—R₁—Z₁— substituted on each Ar orthio to the anhydride group, whereinR₁ is a difunctional organic moiety and Z₁ is a difunctional moietyselected from the group consisting of esters, amides, urethanes,carbamates and carbonates.
 41. The device of claim 40 wherein Ar isFlufenamic Acid, Meclofenamic Acid, Mefenamic Acid, Niflumic Acid,Tolfenamic Acid, Amfenac, Bromfenac, Diclofenac Sodium, Etodolac,Bromosaligenin, Diflunisal, Fendosal, Gentisic Acid, Glycol Salicylate,Mesalamine, Olsalazine, Salicylamide O-Acetic Acid, Salicilic Acid,Sulfasalazine,
 42. The device of claim 36 wherein the polymer isincorporated into a film, paste, gel, fiber, chip, microsphere orscaffolding for cell ingrowth.
 43. The device of claim 40 wherein eachZ₁ is an ester.
 44. The device of claim 27 wherein the agent enhancesbone growth.
 45. A bioactive implant comprising: a polymer filmconfigured to be received in or near the gingival cleft, the filmincluding an anti-inflammatory agent.
 46. The bioactive implant of claim45, wherein the film has a thickness of about 0.1-2.0 mm, a width ofabout 1-5 mm, and a height of about 1-2 mm.
 47. The bioactive implant ofclaim 45, wherein the film is configured to be disposed adjacent to abone.